CA2471723C - Intermediates for lhrh antagonist synthesis, process for their production, and process for lhrh antagonist production - Google Patents
Intermediates for lhrh antagonist synthesis, process for their production, and process for lhrh antagonist production Download PDFInfo
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- CA2471723C CA2471723C CA2471723A CA2471723A CA2471723C CA 2471723 C CA2471723 C CA 2471723C CA 2471723 A CA2471723 A CA 2471723A CA 2471723 A CA2471723 A CA 2471723A CA 2471723 C CA2471723 C CA 2471723C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
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Abstract
The novel tripeptides Ac-D-2Nal-D-4ClPh-D-3Pal-OH and Boc-D-2Nal-D-4ClPhe-D-3Pal-OH are intermediates useful in the synthesis of LHRH analogs by coupling with suitable heptapeptides, in particular with the heptapeptides P1-Ser(P2)-NMeTyr(P3)-D-Lys(Nic)-Leu-Lys(iPr,P4)-Pro-D-AlaNH2 and P1-Ser(P2)-NMeTyr(P3)-D-Asn-Leu-Lys(iPr,P4)-Pro-D-AlaNH2.
Description
INTERMEDIATES FOR LHRH ANTAGONIST SYNTHESIS, PROCESS FOR
THEIR PRODUCTION, AND PROCESS FOR LHRH ANTAGONIST PRODUCTION
FIELD OF THE INVENTION
The present invention relates to intermediates for the synthesis of LHRH antagonists, to a process for the production of these intermediates and to a process for the production of LHRH antagonists.
BACKGROUND OF THE INVENTION
The luteinizing hormone-releasing hormone, LHRH, controls the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH). LHRH antagonists are compounds capable of blocking the secretion of FSH and LH. They are generally nona- and decapeptides (but may be shorter or longer) comprising part of or the entire structure of LHRH in which one or several amino acids have been exchanged for other natural amino acids and/or amino acids not found in nature.
Synthetic LHRH antagonists may be used for contraception and in the treatment of benign hyperplasia of the prostate gland, hormonal-dependent tumors of the breast and ovaries, dysmenorrhea, endometriosis, and other conditions. These synthetic LHRH antagonists have the general formula Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-X-NH2r wherein X is from 5 to 6 natural and/or synthetic amino acid residues. More particularly they have the aforementioned general formula wherein X is AAl-AA2-Leu-AA3-Pro-D-Ala, in particular wherein AA1 is a natural or synthetic amino acid and AA2 is a natural or synthetic amino acid or zero, AA3 is a natural or synthetic amino acid.
While there are a number of synthetic methods for preparing LHRH analogs known in the art, there is a need for improvement since the total yield of LHRH analogs obtained from known processes is not high and the products, in addition, may require extensive purification. Moreover, the methods for the synthesis of LHRH analogs known in the art are quite costly.
A synthesis strategy disclosed in U.S. patent no. 5,710,246 for making decapeptide or nonapeptide LHRH antagonists comprises the coupling of an intermediate tripeptide representing amino residues 1 to 3 (counting starts at the amino terminal of the peptide) with a heptapeptide or a hexapeptide, respectively representing amino acid residues 4-10 and 4-9, respectively. The intermediate tripeptide disclosed in US 5710246 A is an ester, Boc-D-2Nal-D-4ClPhe-D-3Pal-O-Me or the corresponding benzyl or allyl ester.
OBJECTS OF THE INVENTION
It is thus an object of the invention to provide a tripeptide intermediate for the 3+7 and 3+6 synthesis of LHRH analogs in which the yield and/or purity of the product is improved.
It is another object of the invention to provide a process for the production of such a tripeptide intermediate.
THEIR PRODUCTION, AND PROCESS FOR LHRH ANTAGONIST PRODUCTION
FIELD OF THE INVENTION
The present invention relates to intermediates for the synthesis of LHRH antagonists, to a process for the production of these intermediates and to a process for the production of LHRH antagonists.
BACKGROUND OF THE INVENTION
The luteinizing hormone-releasing hormone, LHRH, controls the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH). LHRH antagonists are compounds capable of blocking the secretion of FSH and LH. They are generally nona- and decapeptides (but may be shorter or longer) comprising part of or the entire structure of LHRH in which one or several amino acids have been exchanged for other natural amino acids and/or amino acids not found in nature.
Synthetic LHRH antagonists may be used for contraception and in the treatment of benign hyperplasia of the prostate gland, hormonal-dependent tumors of the breast and ovaries, dysmenorrhea, endometriosis, and other conditions. These synthetic LHRH antagonists have the general formula Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-X-NH2r wherein X is from 5 to 6 natural and/or synthetic amino acid residues. More particularly they have the aforementioned general formula wherein X is AAl-AA2-Leu-AA3-Pro-D-Ala, in particular wherein AA1 is a natural or synthetic amino acid and AA2 is a natural or synthetic amino acid or zero, AA3 is a natural or synthetic amino acid.
While there are a number of synthetic methods for preparing LHRH analogs known in the art, there is a need for improvement since the total yield of LHRH analogs obtained from known processes is not high and the products, in addition, may require extensive purification. Moreover, the methods for the synthesis of LHRH analogs known in the art are quite costly.
A synthesis strategy disclosed in U.S. patent no. 5,710,246 for making decapeptide or nonapeptide LHRH antagonists comprises the coupling of an intermediate tripeptide representing amino residues 1 to 3 (counting starts at the amino terminal of the peptide) with a heptapeptide or a hexapeptide, respectively representing amino acid residues 4-10 and 4-9, respectively. The intermediate tripeptide disclosed in US 5710246 A is an ester, Boc-D-2Nal-D-4ClPhe-D-3Pal-O-Me or the corresponding benzyl or allyl ester.
OBJECTS OF THE INVENTION
It is thus an object of the invention to provide a tripeptide intermediate for the 3+7 and 3+6 synthesis of LHRH analogs in which the yield and/or purity of the product is improved.
It is another object of the invention to provide a process for the production of such a tripeptide intermediate.
It is still another object of the invention to provide a process for the production of LHRH analogs in which a tripeptide is coupled to a hepta- or hexapeptide.
Further objects of the invention will become obvious from the following summary of the invention, the description of preferred embodiments, and the appended patent claims.
DEFINITIONS AND ABBREVIATIONS
For definitions and abbreviations used in this application and which are generally accepted in the field of the invention reference is made in particular to US 5710246 A.
SUMMARY OF THE INVENTION
According to the invention is provided a tripeptide representing amino acids 1-3 of an LHRH antagonist, the terminal amino group of which is Boc- or Ac-protected and the terminal carboxyl group of which (that is, the terminal group of amino acid no. 3) is not protected.
According to the invention is disclosed the tripeptide (I) Ac-D-2Nal-D-4ClPhe-D-3Pal-OH (I) which is a useful intermediate in a process for the synthesis of an LHRH antagonist of the general formula (II) Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-X-NH2 (II) wherein X is from 5 to 7 natural and/or synthetic amino acid residues, more preferred AAl-AA2-Leu-AA3-Pro-D-Ala, in particular wherein AAl is a natural or synthetic amino acid and AA2 is a natural or synthetic amino acid or zero, AA3 is a natural or synthetic amino acid.
Still preferred is the use of the tripeptide (I) in the synthesis of a peptide of the general formula (IIa) Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-AAl-AA2-Leu-Lys(iPr)-Pro-D-Ala-NH2 (IIa) , wherein AAl and AA2 have the meaning given above, in particular a LHRH antagonist of the formula (III) Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-MeTyr-D-Lys(Nic)-Leu-Lys(iPr)-Pro-D-Ala-NH2 (III) or, even more preferred, of the formula (IIIa) Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-MeTyr-D-Asn-Leu-Lys(iPr)-Pro-D-Ala-NH2 (IIIa) According to the invention is also disclosed the tripeptide Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX) of same utility.
Furthermore, according to the invention is disclosed a process for preparing a tripeptide of the formula (I) Ac-D-2Nal-D-4ClPhe-D-3Pal-OH (I) or (IX) Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX), 5 comprising the following consecutive steps for the preparation of (I):
(a) Reacting Boc-D-4ClPhe-OH with HONSu to form Boc-D-4ClPhe-OSu (VII);
(b) Reacting Boc-D-4ClPhe-OSu (VII) with H-D-3Pal-OH to form Boc-D-4ClPhe-D-3Pal-OH (VIII);
(c) Reacting Boc-D-4ClPhe-D-3Pal-OH (VIII) with Boc-D-2Nal-OSu prepared by reacting Boc-D-2Nal-OH with HONSu to form Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX);
(d) Reacting Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX) with acetic acid to form Ac-D-2Nal-4ClPhe-D-3Pal-OH (I);
or the consecutive steps (a) through (c) for the preparation of (IX).
The process of the invention for preparing a LHRH antagonist comprises the step of coupling the tripeptide (I) with a heptapeptide (IV) of the general formula P1-Ser (P2) -AAl-AA2-Leu-Lys (iPr, P4) -Pro-D-AlaNH2 (IV) , wherein P4 is H or an amino protecting group such as Boc, wherein AAl and AA2 have the aforementioned meaning, in particular with a heptapeptide (V) of the general formula P1-Ser (P2) -NMeTyr (P3) -D-Lys (Nic) -Leu-Lys (iPr, P4) -Pro-D-AlaNH2 (V), wherein P1 is selected from H or amino protecting group and P2 and P3 are independently selected from H and -OH
protecting group, and P4 has the meaning given above, for preparing the LHRH antagonist Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-MeTyr-D-Lys(Nic)-Leu-Lys(iPr)-Pro-D-Ala-NH2 (III), more particularly with a heptapeptide (Va) of the general formula Pl-Ser (P2) -NMeTyr (P3) -D-Asn-Leu-Lys (iPr, P4) -Pro-D-AlaNH2 (Va), wherein P1 is selected.from H or amino protecting group and P2 and P3 are independently selected from H and -OH
protecting group, and P4 has the meaning given above, for preparing the LHRH antagonist Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-MeTyr-D-Asn-Leu- Lys(iPr)-Pro-D-Ala-NH2 (III).
The heptapeptide (V) is described in US 5710246 A. The heptapeptide of the general formula (IV) including the heptapeptide (Va) can be synthesized by routine modifications of the synthesis of (V) or by coupling the corresponding Boc-amino acids on a peptide synthesizer (Beckman Model 990), as described in WO 94/40757 where also the LHRH antagonist (III) is disclosed.
Alternatively the process of the invention for preparing a LHRH antagonist comprises the step of coupling the tripeptide (IX) Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX) with a heptapeptide (IV) of the general formula P1-Ser (P2) -AAl-AA2-Leu-Lys (iPr, P4) -Pro-D-AlaNH2 (IV) , wherein P', P2, P4, AA1 and AA2 have the meaning given above, in particular with a heptapeptide (V) of the general formula P1-Ser (P2) -NMeTyr (P3) -D-Lys (Nic) -Leu-Lys (iPr, P4) -Pro-D-AlaNH2 (V) or, even more preferred, with a heptapeptide of the general formula (Va) Pl-Ser (P2) -NMeTyr (P3) -D-Asn-Leu-Lys (iPr, P4) -Pro-D-AlaNH2 (Va), wherein P1 is selected from H or amino protecting group, P2 and P3 are independently selected from H and -OH protecting group, P4 has the aforementioned meaning, followed by substituting the N-terminal Boc group by an acyl group, in particular an acetyl group.
More particularly, the heptapeptide of the general formula (V) is the heptapeptide (VI) H-Ser(tBu)-NMeTyr-D-Lys(Nic)-Leu-Lys(iPr,Boc)-Pro-D-AlaNH2 (VI)A
or even more preferred, the heptapeptide (VIa) H-Ser (tBu) -NMeTyr-D-Asn-Leu-Lys (iPr, Boc) -Pro-D-AlaNH2 (VIa).
A particular advantage with the method of the invention is that a cheaper starting material, H-D-Pal-OH=2HC1, can be used instead of the ester H-Pal-OR=2HC1; the protective group of the starting material need not be removed. Therefore the synthesis of the invention is one step shorter and avoids that material is lost in the additional step. Another advantage is that the formation of impurities in the saponification step is avoided. The formation of such impurities is well known. For instance, the basic conditions at the ester hydrolysis step cause partial racemization of D-Pal. The other prior-art alternative of removing the ester group by catalytic hydrogenation (in the case of allyl or benzyl ester groups) risks to cause a loss of Cl from 4ClPhe producing Phe. While allyl groups may be removed by still other reagents the full removal is.difficult to control.
7a The present invention provides a process for preparing a tripeptide, including a salt thereof, of the formula (IX) Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX) comprising the following consecutive steps:
(a) Reacting Boc-D-4ClPhe-OH with HONSu to form Boc-D-4ClPhe-OSu (VII);
(b) Reacting Boc-D-4ClPhe-OSu (VII) with H-D-3Pal-OH to form Boc-D-4CIPhe-D-3Pal-OH (VIII); and (c) Deprotecting Boc-D-4ClPhe-D-3Pal-OH (VIII) and reacting with Boc-D-2Nal-OSu prepared by reacting Boc-2Nal-OH with HONSu to form Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX).
The present invention also provides a process for preparing an LHRH antagonist or a pharmaceutically acceptable salt thereof, wherein the tripeptide Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX) is coupled with a heptapeptide (IV) of the general formula Pl-Ser (P2) -AA1-AA2-Leu-Lys (iPr, P4) -Pro-D-AlaNH2 (IV), wherein P1 is selected from H or amino protecting group, P2 is H or OH-protecting group, P4 is H or an amino protecting group AA1 is natural or synthetic amino acid and AA2 is natural or synthetic amino acid or zero.
The present invention also provides the use of the tripeptide Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX) for preparing an LHRH
antagonist or a pharmaceutically acceptable salt thereof in a process comprising the coupling of the tripeptide (IX) with a heptapeptide P1-Ser (P2) -AAl-AA2-Leu-Lys (iPr, P4) -Pro-D-AlaNH2 (IV).
7b The present invention further provides the use of the tripeptide Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX) for preparing a tripeptide of the formula (I) Ac-D-2Nal-D-4ClPhe-D-3Pal-OH (I) in a process comprising the steps of:
(a) Deprotection by adding water, acetic acid and MSA, followed by neutralization with TEA and concentration in vacuo to give an oil and (b) Acetylation by dissolving the oil in toluene and acetyl imidazole.
Further objects of the invention will become obvious from the following summary of the invention, the description of preferred embodiments, and the appended patent claims.
DEFINITIONS AND ABBREVIATIONS
For definitions and abbreviations used in this application and which are generally accepted in the field of the invention reference is made in particular to US 5710246 A.
SUMMARY OF THE INVENTION
According to the invention is provided a tripeptide representing amino acids 1-3 of an LHRH antagonist, the terminal amino group of which is Boc- or Ac-protected and the terminal carboxyl group of which (that is, the terminal group of amino acid no. 3) is not protected.
According to the invention is disclosed the tripeptide (I) Ac-D-2Nal-D-4ClPhe-D-3Pal-OH (I) which is a useful intermediate in a process for the synthesis of an LHRH antagonist of the general formula (II) Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-X-NH2 (II) wherein X is from 5 to 7 natural and/or synthetic amino acid residues, more preferred AAl-AA2-Leu-AA3-Pro-D-Ala, in particular wherein AAl is a natural or synthetic amino acid and AA2 is a natural or synthetic amino acid or zero, AA3 is a natural or synthetic amino acid.
Still preferred is the use of the tripeptide (I) in the synthesis of a peptide of the general formula (IIa) Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-AAl-AA2-Leu-Lys(iPr)-Pro-D-Ala-NH2 (IIa) , wherein AAl and AA2 have the meaning given above, in particular a LHRH antagonist of the formula (III) Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-MeTyr-D-Lys(Nic)-Leu-Lys(iPr)-Pro-D-Ala-NH2 (III) or, even more preferred, of the formula (IIIa) Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-MeTyr-D-Asn-Leu-Lys(iPr)-Pro-D-Ala-NH2 (IIIa) According to the invention is also disclosed the tripeptide Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX) of same utility.
Furthermore, according to the invention is disclosed a process for preparing a tripeptide of the formula (I) Ac-D-2Nal-D-4ClPhe-D-3Pal-OH (I) or (IX) Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX), 5 comprising the following consecutive steps for the preparation of (I):
(a) Reacting Boc-D-4ClPhe-OH with HONSu to form Boc-D-4ClPhe-OSu (VII);
(b) Reacting Boc-D-4ClPhe-OSu (VII) with H-D-3Pal-OH to form Boc-D-4ClPhe-D-3Pal-OH (VIII);
(c) Reacting Boc-D-4ClPhe-D-3Pal-OH (VIII) with Boc-D-2Nal-OSu prepared by reacting Boc-D-2Nal-OH with HONSu to form Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX);
(d) Reacting Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX) with acetic acid to form Ac-D-2Nal-4ClPhe-D-3Pal-OH (I);
or the consecutive steps (a) through (c) for the preparation of (IX).
The process of the invention for preparing a LHRH antagonist comprises the step of coupling the tripeptide (I) with a heptapeptide (IV) of the general formula P1-Ser (P2) -AAl-AA2-Leu-Lys (iPr, P4) -Pro-D-AlaNH2 (IV) , wherein P4 is H or an amino protecting group such as Boc, wherein AAl and AA2 have the aforementioned meaning, in particular with a heptapeptide (V) of the general formula P1-Ser (P2) -NMeTyr (P3) -D-Lys (Nic) -Leu-Lys (iPr, P4) -Pro-D-AlaNH2 (V), wherein P1 is selected from H or amino protecting group and P2 and P3 are independently selected from H and -OH
protecting group, and P4 has the meaning given above, for preparing the LHRH antagonist Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-MeTyr-D-Lys(Nic)-Leu-Lys(iPr)-Pro-D-Ala-NH2 (III), more particularly with a heptapeptide (Va) of the general formula Pl-Ser (P2) -NMeTyr (P3) -D-Asn-Leu-Lys (iPr, P4) -Pro-D-AlaNH2 (Va), wherein P1 is selected.from H or amino protecting group and P2 and P3 are independently selected from H and -OH
protecting group, and P4 has the meaning given above, for preparing the LHRH antagonist Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-MeTyr-D-Asn-Leu- Lys(iPr)-Pro-D-Ala-NH2 (III).
The heptapeptide (V) is described in US 5710246 A. The heptapeptide of the general formula (IV) including the heptapeptide (Va) can be synthesized by routine modifications of the synthesis of (V) or by coupling the corresponding Boc-amino acids on a peptide synthesizer (Beckman Model 990), as described in WO 94/40757 where also the LHRH antagonist (III) is disclosed.
Alternatively the process of the invention for preparing a LHRH antagonist comprises the step of coupling the tripeptide (IX) Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX) with a heptapeptide (IV) of the general formula P1-Ser (P2) -AAl-AA2-Leu-Lys (iPr, P4) -Pro-D-AlaNH2 (IV) , wherein P', P2, P4, AA1 and AA2 have the meaning given above, in particular with a heptapeptide (V) of the general formula P1-Ser (P2) -NMeTyr (P3) -D-Lys (Nic) -Leu-Lys (iPr, P4) -Pro-D-AlaNH2 (V) or, even more preferred, with a heptapeptide of the general formula (Va) Pl-Ser (P2) -NMeTyr (P3) -D-Asn-Leu-Lys (iPr, P4) -Pro-D-AlaNH2 (Va), wherein P1 is selected from H or amino protecting group, P2 and P3 are independently selected from H and -OH protecting group, P4 has the aforementioned meaning, followed by substituting the N-terminal Boc group by an acyl group, in particular an acetyl group.
More particularly, the heptapeptide of the general formula (V) is the heptapeptide (VI) H-Ser(tBu)-NMeTyr-D-Lys(Nic)-Leu-Lys(iPr,Boc)-Pro-D-AlaNH2 (VI)A
or even more preferred, the heptapeptide (VIa) H-Ser (tBu) -NMeTyr-D-Asn-Leu-Lys (iPr, Boc) -Pro-D-AlaNH2 (VIa).
A particular advantage with the method of the invention is that a cheaper starting material, H-D-Pal-OH=2HC1, can be used instead of the ester H-Pal-OR=2HC1; the protective group of the starting material need not be removed. Therefore the synthesis of the invention is one step shorter and avoids that material is lost in the additional step. Another advantage is that the formation of impurities in the saponification step is avoided. The formation of such impurities is well known. For instance, the basic conditions at the ester hydrolysis step cause partial racemization of D-Pal. The other prior-art alternative of removing the ester group by catalytic hydrogenation (in the case of allyl or benzyl ester groups) risks to cause a loss of Cl from 4ClPhe producing Phe. While allyl groups may be removed by still other reagents the full removal is.difficult to control.
7a The present invention provides a process for preparing a tripeptide, including a salt thereof, of the formula (IX) Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX) comprising the following consecutive steps:
(a) Reacting Boc-D-4ClPhe-OH with HONSu to form Boc-D-4ClPhe-OSu (VII);
(b) Reacting Boc-D-4ClPhe-OSu (VII) with H-D-3Pal-OH to form Boc-D-4CIPhe-D-3Pal-OH (VIII); and (c) Deprotecting Boc-D-4ClPhe-D-3Pal-OH (VIII) and reacting with Boc-D-2Nal-OSu prepared by reacting Boc-2Nal-OH with HONSu to form Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX).
The present invention also provides a process for preparing an LHRH antagonist or a pharmaceutically acceptable salt thereof, wherein the tripeptide Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX) is coupled with a heptapeptide (IV) of the general formula Pl-Ser (P2) -AA1-AA2-Leu-Lys (iPr, P4) -Pro-D-AlaNH2 (IV), wherein P1 is selected from H or amino protecting group, P2 is H or OH-protecting group, P4 is H or an amino protecting group AA1 is natural or synthetic amino acid and AA2 is natural or synthetic amino acid or zero.
The present invention also provides the use of the tripeptide Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX) for preparing an LHRH
antagonist or a pharmaceutically acceptable salt thereof in a process comprising the coupling of the tripeptide (IX) with a heptapeptide P1-Ser (P2) -AAl-AA2-Leu-Lys (iPr, P4) -Pro-D-AlaNH2 (IV).
7b The present invention further provides the use of the tripeptide Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX) for preparing a tripeptide of the formula (I) Ac-D-2Nal-D-4ClPhe-D-3Pal-OH (I) in a process comprising the steps of:
(a) Deprotection by adding water, acetic acid and MSA, followed by neutralization with TEA and concentration in vacuo to give an oil and (b) Acetylation by dissolving the oil in toluene and acetyl imidazole.
The invention will now be explained in more detail by reference to a preferred embodiment.
DESCRIPTION OF A PREFERRED EMBODIMENT OF THE INVENTION
Synthesis of Ac-D-2Na1-4ClPhe-D-3Pa1-OH M.
EXAMPLE 1. Boc-D-4ClPhe-OSu. Boc-D-4ClPhe-OH (299,75 g; 1,0 eq.) and-HONSu (184,1 g; 1,6 eq.) are dissolved in 2-propanol (4,5 L) . The mixture is cooled to 0 C and DIC (164,1 g; 1.3 eq.) is added. The mixture is stirred for 16h while warming to room temperature. The product is filtered of, washed with 2-propanol (1,5 L) and dried. Yield: 85%. HPLC purity: 98,8%.
EXAMPLE 2. Boc-D-4ClPhe-D-3Pal-OH. H-D-3Pal-OH, 2 HC1 (251,1 g; 1,05 eq.) and Boc-D-4ClPhe-OSu (396,8 g; 1,0 eq.) are dissolved in DMSO (3,33 L) and NMM (318,8 g; 3,15 eq.) is added. The mixture is stirred for 16 h at room temperature.
Water (17 L) is added and pH is adjusted to 4-4,5 which causes the product to precipitate. The mixture is filtered and the product is washed with water (3 x 5 L) to remove traces of DMSO, H-D-3Pal-OH and Boc-D-4ClPhe-OH. The product is dried. Yield: 80%. HPLC purity:.97,8%
EXAMPLE 3. Boc-D-2Nal-OSu. Boc-D-2Nal-OH (315,4 g; 1,0 eq.) is dissolved in 2-propanol (6,8 L)`at -10 C and IBC (157 g;
1,15 eq.) and NMM (116 g; 1,15 eq.) is added. After stirring for 5-10 min a mixture of HONSu (230,1 g; 2,0 eq.) in 2-propanol (1,4 L) is added. Additional NMM (10,1 g; 0,1 eq.) is added. After half an hour water (0,82 L) is added to dissolve precipitated NMM=HC1. The product is isolated by filtration, washed with 2-propanol (1 L), and dried. Yield:
90%. HPLC purity: 98,3%.
EXAMPLE 4. Boc-D-Nal-D-4ClPhe-D-3Pal-OH.
(a) Deprotection. Boc-D-4ClPhe-D-3Pal-OH (447,93 g; 1,0 eq.) is dissolved in a mixture of ethyl acetate (3,4 L), acetic acid (675 ml) and MSA (454 mL; 7,0 eq.) at 0 C and kept at this temperature for two hours. TEA (1669 ml; 12 eq.) is added.
b) Condensation. Boc-D-Nal-OSu (412,4 g; 1,0 eq.) is added to the neutralized deprotection mixture at room temperature. The reaction mixture is kept at this temperature for 2-4 h. Aq.
25% NH3 (154 mL; 2,0 eq.) is added to quench remaining hydroxysuccinimide ester. 1-Butanol (4,5 L) is added to prevent precipitation in the subsequent extractions.
c) Purification and isolation. The reaction mixture is extracted twice at pH 6 (2 x 4,5 L water) to remove TEA, at pH 9 (4,5 L water) to remove MSA and finally at pH 7 (4,5 L
water). The extractions are carried out at 40-45 C to prevent precipitation. To the organic phase is added acetic acid (4,5 L'; 1 vol.) and the mixture is concentrated in vacuo and co-evaporated with acetic acid (4,5 L) to give a solid.
EXAMPLE 5. Ac-D-2Nal-D-4ClPhe-D-3Pal-ONa. .
a) Deprotection. To the solid Boc-D-2Nal-D-4ClPhe-D-3Pal-OH is added water (90 ml), acetic acid (1,8 L) and MSA (454 mL; 7,0 eq.) and the mixture is stirred for 1-2 h at room temperature.
The mixture is cooled to 0 C and neutralized with TEA (1071 ml;
7,7 eq.). The solution is concentrated in vacuo and co-evaporated twice with toluene (2 x 2,5 L) to give an oil.
b) Acetylation. The oil from the deprotection step is dissolves in toluene (2,0 L) and acetyl imidazole (132,14 g) is added.
The mixture is stirred at room temperature for 1 h and then water (100 ml) is added to quench remaining acetyl imidazole.
d) Purification. The mixture from the acetylation is heated to 30-35 C and 1-butanol (4,5 L) is added to prevent precipitation 5 The mixture is extracted twice at pH 5 (2 x 2,6 L water), and twice at pH 11 (2 x 2,6 L water) using NaOH to adjust pH to 11.
Methanol (2,25 L) is added to the last extractions to prevent precipitation. NaCl (130 g) is added to the first and the last extraction to minimize loss of product in the aqueous phases.
DESCRIPTION OF A PREFERRED EMBODIMENT OF THE INVENTION
Synthesis of Ac-D-2Na1-4ClPhe-D-3Pa1-OH M.
EXAMPLE 1. Boc-D-4ClPhe-OSu. Boc-D-4ClPhe-OH (299,75 g; 1,0 eq.) and-HONSu (184,1 g; 1,6 eq.) are dissolved in 2-propanol (4,5 L) . The mixture is cooled to 0 C and DIC (164,1 g; 1.3 eq.) is added. The mixture is stirred for 16h while warming to room temperature. The product is filtered of, washed with 2-propanol (1,5 L) and dried. Yield: 85%. HPLC purity: 98,8%.
EXAMPLE 2. Boc-D-4ClPhe-D-3Pal-OH. H-D-3Pal-OH, 2 HC1 (251,1 g; 1,05 eq.) and Boc-D-4ClPhe-OSu (396,8 g; 1,0 eq.) are dissolved in DMSO (3,33 L) and NMM (318,8 g; 3,15 eq.) is added. The mixture is stirred for 16 h at room temperature.
Water (17 L) is added and pH is adjusted to 4-4,5 which causes the product to precipitate. The mixture is filtered and the product is washed with water (3 x 5 L) to remove traces of DMSO, H-D-3Pal-OH and Boc-D-4ClPhe-OH. The product is dried. Yield: 80%. HPLC purity:.97,8%
EXAMPLE 3. Boc-D-2Nal-OSu. Boc-D-2Nal-OH (315,4 g; 1,0 eq.) is dissolved in 2-propanol (6,8 L)`at -10 C and IBC (157 g;
1,15 eq.) and NMM (116 g; 1,15 eq.) is added. After stirring for 5-10 min a mixture of HONSu (230,1 g; 2,0 eq.) in 2-propanol (1,4 L) is added. Additional NMM (10,1 g; 0,1 eq.) is added. After half an hour water (0,82 L) is added to dissolve precipitated NMM=HC1. The product is isolated by filtration, washed with 2-propanol (1 L), and dried. Yield:
90%. HPLC purity: 98,3%.
EXAMPLE 4. Boc-D-Nal-D-4ClPhe-D-3Pal-OH.
(a) Deprotection. Boc-D-4ClPhe-D-3Pal-OH (447,93 g; 1,0 eq.) is dissolved in a mixture of ethyl acetate (3,4 L), acetic acid (675 ml) and MSA (454 mL; 7,0 eq.) at 0 C and kept at this temperature for two hours. TEA (1669 ml; 12 eq.) is added.
b) Condensation. Boc-D-Nal-OSu (412,4 g; 1,0 eq.) is added to the neutralized deprotection mixture at room temperature. The reaction mixture is kept at this temperature for 2-4 h. Aq.
25% NH3 (154 mL; 2,0 eq.) is added to quench remaining hydroxysuccinimide ester. 1-Butanol (4,5 L) is added to prevent precipitation in the subsequent extractions.
c) Purification and isolation. The reaction mixture is extracted twice at pH 6 (2 x 4,5 L water) to remove TEA, at pH 9 (4,5 L water) to remove MSA and finally at pH 7 (4,5 L
water). The extractions are carried out at 40-45 C to prevent precipitation. To the organic phase is added acetic acid (4,5 L'; 1 vol.) and the mixture is concentrated in vacuo and co-evaporated with acetic acid (4,5 L) to give a solid.
EXAMPLE 5. Ac-D-2Nal-D-4ClPhe-D-3Pal-ONa. .
a) Deprotection. To the solid Boc-D-2Nal-D-4ClPhe-D-3Pal-OH is added water (90 ml), acetic acid (1,8 L) and MSA (454 mL; 7,0 eq.) and the mixture is stirred for 1-2 h at room temperature.
The mixture is cooled to 0 C and neutralized with TEA (1071 ml;
7,7 eq.). The solution is concentrated in vacuo and co-evaporated twice with toluene (2 x 2,5 L) to give an oil.
b) Acetylation. The oil from the deprotection step is dissolves in toluene (2,0 L) and acetyl imidazole (132,14 g) is added.
The mixture is stirred at room temperature for 1 h and then water (100 ml) is added to quench remaining acetyl imidazole.
d) Purification. The mixture from the acetylation is heated to 30-35 C and 1-butanol (4,5 L) is added to prevent precipitation 5 The mixture is extracted twice at pH 5 (2 x 2,6 L water), and twice at pH 11 (2 x 2,6 L water) using NaOH to adjust pH to 11.
Methanol (2,25 L) is added to the last extractions to prevent precipitation. NaCl (130 g) is added to the first and the last extraction to minimize loss of product in the aqueous phases.
10 e) Isolation. To the vigorously stirred organic phase from the extractions is added heptane (15 L) and the resulting suspension is left at room temperature while stirring for at least 1 h. The mixture is filtered and the product is washed twice with heptane (2 x 3,5 L) and dried. Yield: 75% (from Boc-D-4ClPhe-D-3Pal-OH). HPLC purity: 92%. Amino acid analysis:
2Nal: 1.1; 4ClPhe: 1.0; 3Pal: 0.9. MS: MW 586. Na: 4.6%
EXAMPLE 6. Ac-D-2Nal-D-4ClPhe-D-3Pal-OH=DCHA
a) Deprotection. To the solid Boc-D-2Nal-D-4ClPhe-D-3Pal-OH
is added water (90 mL), acetic acid (1,8 L) and MSA (454 mL;
7,0 eq.) and the mixture is stirred for 1-2 h at room temperature. The mixture is cooled to 0 C and neutralized with TEA (1071 mL; 7,7 eq.). The solution is concentrated in vacuo and co-evaporated twice with toluene (2 x 2,5 L) to give an oil.
b) Acetylation. The oil from the deprotection is dissolved in toluene (2,0 L) and acetyl imidazole (132,14 g) is added. The mixture is stirred at room temperature for 1 h followed by addition of water (100 ml) to quench remaining acetyl imidazole.
c) Purification. The mixture is heated to 30-35 C and 1-butanol (4,5 L) is added to prevent precipitation. The mixture is extracted twice at pH 7 (2 x 2,6 L water), once at pH 9-9,5 (2,6 L water) and once at pH 7 (2,6 L water). DCHA
(dicyclohexyl amine) is added and the mixture is concentrated in vacuo. The product is suspended in 1-butanol (4,5 L) at 50 C
and slowly added to vigorously stirred heptane (27 L). The mixture is stirred at 0 C over night, filtered and the product washed twice with 1-butanol/heptane (1:3; 2x4,8 L) and twice with heptane (2x4,5 L). Yield: 65% (from Boc-D-4ClPhe-D-3Pal-OH). HPLC purity: 94,2%. Amino acid analysis: 2Nal: 1.1;
4ClPhe: 1.0; 3Pal: 0.9. MS: MW 586 (free peptide).
EXAMPLE 7. Ac-D-2Nal-D-4ClPhe-D-3Pal-OH.
a) Deprotection. To the solid Boc-D-2Nal-D-4ClPhe-D-3Pal-OH is added water (90 mL), acetic acid (1,8 L) and MSA (454 ml; 7,0 eq.) and the mixture is stirred for 1-2 h at room temperature.
The mixture is cooled to 0 C and neutralized with TEA (1071 mL;
7,7 eq.). The solution is concentrated in vacuo and co-evaporated twice with toluene (2 x 2,5 L) to give an oil.
b) Acetylation. The oil from the deprotection is dissolved in toluene (2,0 L) and acetyl imidazole (132,14 g) is added. The mixture is stirred at room temperature for 1 h and then water (100 mL) is added to quench remaining acetyl imidazole.
c) Purification. The mixture from the acetylation is heated to 30-35 C and 1-butanol (4,5 L) is added to prevent precipitation The mixture is extracted twice at pH = 7 (2 x 2,6 L water), anc once at pH = 9-9,5 (2,6 L water) and once at pH=7 (2,6 L
water). The mixture is concentrated in vacuo to an oil, which is dissolved in acetic acid (750 ml), concentrated, re-dissolved in acetic acid (750 ml) and slowly added to vigorously stirred heptane/ethyl acetate (3:1; 3,6 L). The mixture is left with stirring at 0 C over night. The mixture is filtered, and the product is washed twice with ethyl acetate/
heptane (1:3; 2x3,6 L) and twice with heptane (2x3,6 L).
2Nal: 1.1; 4ClPhe: 1.0; 3Pal: 0.9. MS: MW 586. Na: 4.6%
EXAMPLE 6. Ac-D-2Nal-D-4ClPhe-D-3Pal-OH=DCHA
a) Deprotection. To the solid Boc-D-2Nal-D-4ClPhe-D-3Pal-OH
is added water (90 mL), acetic acid (1,8 L) and MSA (454 mL;
7,0 eq.) and the mixture is stirred for 1-2 h at room temperature. The mixture is cooled to 0 C and neutralized with TEA (1071 mL; 7,7 eq.). The solution is concentrated in vacuo and co-evaporated twice with toluene (2 x 2,5 L) to give an oil.
b) Acetylation. The oil from the deprotection is dissolved in toluene (2,0 L) and acetyl imidazole (132,14 g) is added. The mixture is stirred at room temperature for 1 h followed by addition of water (100 ml) to quench remaining acetyl imidazole.
c) Purification. The mixture is heated to 30-35 C and 1-butanol (4,5 L) is added to prevent precipitation. The mixture is extracted twice at pH 7 (2 x 2,6 L water), once at pH 9-9,5 (2,6 L water) and once at pH 7 (2,6 L water). DCHA
(dicyclohexyl amine) is added and the mixture is concentrated in vacuo. The product is suspended in 1-butanol (4,5 L) at 50 C
and slowly added to vigorously stirred heptane (27 L). The mixture is stirred at 0 C over night, filtered and the product washed twice with 1-butanol/heptane (1:3; 2x4,8 L) and twice with heptane (2x4,5 L). Yield: 65% (from Boc-D-4ClPhe-D-3Pal-OH). HPLC purity: 94,2%. Amino acid analysis: 2Nal: 1.1;
4ClPhe: 1.0; 3Pal: 0.9. MS: MW 586 (free peptide).
EXAMPLE 7. Ac-D-2Nal-D-4ClPhe-D-3Pal-OH.
a) Deprotection. To the solid Boc-D-2Nal-D-4ClPhe-D-3Pal-OH is added water (90 mL), acetic acid (1,8 L) and MSA (454 ml; 7,0 eq.) and the mixture is stirred for 1-2 h at room temperature.
The mixture is cooled to 0 C and neutralized with TEA (1071 mL;
7,7 eq.). The solution is concentrated in vacuo and co-evaporated twice with toluene (2 x 2,5 L) to give an oil.
b) Acetylation. The oil from the deprotection is dissolved in toluene (2,0 L) and acetyl imidazole (132,14 g) is added. The mixture is stirred at room temperature for 1 h and then water (100 mL) is added to quench remaining acetyl imidazole.
c) Purification. The mixture from the acetylation is heated to 30-35 C and 1-butanol (4,5 L) is added to prevent precipitation The mixture is extracted twice at pH = 7 (2 x 2,6 L water), anc once at pH = 9-9,5 (2,6 L water) and once at pH=7 (2,6 L
water). The mixture is concentrated in vacuo to an oil, which is dissolved in acetic acid (750 ml), concentrated, re-dissolved in acetic acid (750 ml) and slowly added to vigorously stirred heptane/ethyl acetate (3:1; 3,6 L). The mixture is left with stirring at 0 C over night. The mixture is filtered, and the product is washed twice with ethyl acetate/
heptane (1:3; 2x3,6 L) and twice with heptane (2x3,6 L).
Yield: 70% (from Boc-D-4ClPhe-D-3Pal-OH). HPLC purity: 93,9%.
Amino acid analysis: Nal: 1.1; 4ClPhe: 1.0; 3Pal: 0.9 MS: MW 586 (free peptide).
Amino acid analysis: Nal: 1.1; 4ClPhe: 1.0; 3Pal: 0.9 MS: MW 586 (free peptide).
Claims (12)
1. A process for preparing a tripeptide, including a salt thereof, of the formula (IX) Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX) comprising the following consecutive steps:
(a) Reacting Boc-D-4ClPhe-OH with HONSu to form Boc-D-4ClPhe-OSu (VII);
(b) Reacting Boc-D-4ClPhe-OSu (VII) with H-D-3Pal-OH to form Boc-D-4ClPhe-D-3Pal-OH (VIII); and (c) Deprotecting Boc-D-4ClPhe-D-3Pal-OH (VIII) and reacting with Boc-D-2Nal-OSu prepared by reacting Boc-2Nal-OH with HONSu to form Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX).
(a) Reacting Boc-D-4ClPhe-OH with HONSu to form Boc-D-4ClPhe-OSu (VII);
(b) Reacting Boc-D-4ClPhe-OSu (VII) with H-D-3Pal-OH to form Boc-D-4ClPhe-D-3Pal-OH (VIII); and (c) Deprotecting Boc-D-4ClPhe-D-3Pal-OH (VIII) and reacting with Boc-D-2Nal-OSu prepared by reacting Boc-2Nal-OH with HONSu to form Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX).
2. A process for preparing an LHRH antagonist or a pharmaceutically acceptable salt thereof, wherein the tripeptide Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX) is coupled with a heptapeptide (IV) of the general formula Pl-Ser(P2)-AA1-AA2-Leu-Lys (iPr, P4)-Pro-D-AlaNH2 (IV), wherein P1 is selected from H or amino protecting group, P2 is H or OH-protecting group, P4 is H or an amino protecting group AA1 is natural or synthetic amino acid and AA2 is natural or synthetic amino acid or zero.
3. The process of claim 2, wherein the amino protecting group is Boc.
4. The process of claim 2, wherein the heptapeptide of the general formula (IV) is P1-Ser(P2)-NMeTyr(P3)-D-Lys(Nic)-Leu-Lys(iPr,P4)-Pro-D-AlaNH2 (V) wherein P3 is H or -OH protecting group.
5. The process of claim 4, wherein the heptapeptide of the general formula (V) is H-Ser(tBu)-NMeTyr-D-Lys(Nic)-Leu-Lys (iPr, Boc) -Pro-D-AlaNH2 (VI).
6. The process of claim 2, wherein the heptapeptide of the general formula (IV) is P1-Ser(P2)-NMeTyr(P3)-D-Asn-Leu-Lys(iPr, P4)-Pro-D-AlaNH2(Va), followed by substituting the Boc group by an acyl group.
7. The process of claim 6, wherein the acyl group is an acetyl group.
8. The process of claim 6, wherein the heptapeptide of the general formula (IV) is H-Ser(tBu)-NMeTyr-D-Asn-Leu-Lys(iPr,Boc)-Pro-D-AlaNH2 (Vla).
followed by substituting the N-terminal Boc group by an acyl group.
followed by substituting the N-terminal Boc group by an acyl group.
9. The process of claim 8, wherein the acyl group is an acetyl group.
10. The tripeptide Boc-D-2Nal-D-4C1Phe-D-3Pal-OH (IX) or a salt thereof.
11. Use of the tripeptide Boc-D-2Nal-D-4C1Phe-D-3Pa1-OH
(IX) for preparing an LHRH antagonist or a pharmaceutically acceptable salt thereof in a process comprising the coupling of the tripeptide (IX) with a heptapeptide P1-Ser(P2)-AA1-AA2-Leu-Lys (iPr, P4)-Pro-D-AlaNH2 (IV).
(IX) for preparing an LHRH antagonist or a pharmaceutically acceptable salt thereof in a process comprising the coupling of the tripeptide (IX) with a heptapeptide P1-Ser(P2)-AA1-AA2-Leu-Lys (iPr, P4)-Pro-D-AlaNH2 (IV).
12. Use of the tripeptide Boc-D-2Nal-D-4ClPhe-D-3Pal-OH
(IX) for preparing a tripeptide of the formula (I) Ac-D-2Nal-D-4ClPhe-D-3Pal-OH (I) in a process comprising the steps of:
(a) Deprotection by adding water, acetic acid and MSA, followed by neutralization with TEA and concentration in vacuo to give an oil and (b) Acetylation by dissolving the oil in toluene and acetyl imidazole.
(IX) for preparing a tripeptide of the formula (I) Ac-D-2Nal-D-4ClPhe-D-3Pal-OH (I) in a process comprising the steps of:
(a) Deprotection by adding water, acetic acid and MSA, followed by neutralization with TEA and concentration in vacuo to give an oil and (b) Acetylation by dissolving the oil in toluene and acetyl imidazole.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE0104463A SE0104463D0 (en) | 2001-12-29 | 2001-12-29 | Intermediates for Synthesis of LHRH Antagonists, Methods of Preparation and Methods for Preparation of LHRH Antagonists |
| SE0104463-5 | 2001-12-29 | ||
| PCT/IB2002/005583 WO2003055902A1 (en) | 2001-12-29 | 2002-12-23 | Intermediates for lhrh antagonist synthesis, process for their production, and process for lhrh antagonist production |
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| CA2471723A1 CA2471723A1 (en) | 2003-07-10 |
| CA2471723C true CA2471723C (en) | 2011-02-15 |
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| CA2471723A Expired - Fee Related CA2471723C (en) | 2001-12-29 | 2002-12-23 | Intermediates for lhrh antagonist synthesis, process for their production, and process for lhrh antagonist production |
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| Country | Link |
|---|---|
| US (2) | US20050124788A1 (en) |
| EP (2) | EP1630169B1 (en) |
| JP (1) | JP4272529B2 (en) |
| KR (1) | KR100844520B1 (en) |
| CN (1) | CN1304417C (en) |
| AT (2) | ATE342913T1 (en) |
| AU (1) | AU2002348749B2 (en) |
| CA (1) | CA2471723C (en) |
| CY (2) | CY1107580T1 (en) |
| DE (2) | DE60215544T2 (en) |
| DK (2) | DK1630169T3 (en) |
| ES (2) | ES2296050T3 (en) |
| HK (1) | HK1075052A1 (en) |
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| PT (2) | PT1465917E (en) |
| RU (1) | RU2307125C2 (en) |
| SE (1) | SE0104463D0 (en) |
| SI (1) | SI1630169T1 (en) |
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| JP4407322B2 (en) | 2004-03-09 | 2010-02-03 | 味の素株式会社 | Method for producing peptide |
| CN101037472B (en) * | 2006-03-14 | 2013-03-27 | 中国人民解放军军事医学科学院毒物药物研究所 | LHRH antagonist with low-histamine releasing function |
| TWI539959B (en) | 2008-02-11 | 2016-07-01 | 菲瑞茵國際中心股份有限公司 | Method of treating metastatic stage prostate cancer |
| SI2632934T1 (en) | 2010-10-27 | 2017-02-28 | Ferring B.V. | Process for the manufacture of degarelix and its intermediates |
| EP2447276A1 (en) * | 2010-10-27 | 2012-05-02 | Ferring B.V. | Process for the manufacture of Degarelix and its intermediates |
| MY182320A (en) | 2012-06-01 | 2021-01-19 | Ferring Bv | Downstream process |
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| US4098777A (en) * | 1977-03-14 | 1978-07-04 | Merck & Co., Inc. | Process for the preparation of pyroglutamyl-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn |
| US5225598A (en) * | 1990-03-30 | 1993-07-06 | Union Carbide Chemicals & Plastics Technology Corporation | Selective production of linear pentaethylenehexamine and hydroxyethyldiethylenetriamine |
| EP0540626A1 (en) * | 1990-07-24 | 1993-05-12 | Eastman Chemical Company | Process for synthesizing peptides |
| US5710246A (en) * | 1996-03-19 | 1998-01-20 | Abbott Laboratories | Process for intermediates for the synthesis of LHRH antagonists |
| ES2264169T3 (en) * | 1996-10-30 | 2006-12-16 | Pfizer Inc. | AZABICICLIC DERIVATIVES OF PIRIDONA FUSIONADA OR CITISINA, ITS PREPARATION AND ITS USE IN THE ADDICTION THERAPY. |
| US5968895A (en) * | 1996-12-11 | 1999-10-19 | Praecis Pharmaceuticals, Inc. | Pharmaceutical formulations for sustained drug delivery |
| DE19941248A1 (en) | 1998-09-01 | 2000-03-02 | Asta Medica Ag | New cetrorelix analogs containing N-substituted glycine derivatives useful as LHRH antagonists, e.g. for treating hormone-dependent tumors |
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- 2002-12-23 US US10/500,047 patent/US20050124788A1/en not_active Abandoned
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- 2002-12-23 WO PCT/IB2002/005583 patent/WO2003055902A1/en active Search and Examination
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- 2002-12-23 IL IL16278802A patent/IL162788A0/en unknown
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- 2002-12-23 AT AT05025717T patent/ATE371666T1/en active
- 2002-12-23 PT PT05025717T patent/PT1630169E/en unknown
- 2002-12-23 SI SI200230642T patent/SI1630169T1/en unknown
- 2002-12-23 NZ NZ534245A patent/NZ534245A/en not_active IP Right Cessation
- 2002-12-23 DK DK02781699T patent/DK1465917T3/en active
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2004
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- 2004-07-16 NO NO20043047A patent/NO330129B1/en not_active IP Right Cessation
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2005
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2007
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2008
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